ORCID Profile
0000-0002-4150-1077
Current Organisations
KU Leuven
,
Beatson Institute for Cancer Research
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Publisher: American Association for the Advancement of Science (AAAS)
Date: 05-02-2019
DOI: 10.1126/SCISIGNAL.AAN8247
Abstract: Analysis of the cancer-associated fibroblast secretome identifies an angiogenesis-promoting factor.
Publisher: EMBO
Date: 10-07-2017
Publisher: Springer Science and Business Media LLC
Date: 24-09-2018
Publisher: Cold Spring Harbor Laboratory
Date: 27-11-2019
DOI: 10.1101/851410
Abstract: The signalling pathways underpinning cell growth and invasion use overlapping components, yet how mutually exclusive cellular responses occur is unclear. We developed 3-Dimensional culture analyses to separately quantify growth and invasion. We identify that alternate variants of IQSEC1, an ARF GTPase Exchange Factor, act as switches to promote invasion over growth by spatially enriching cortical phosphoinositide metabolism. All IQSEC1 variants activate ARF5- and ARF6-dependent PIP5-kinase to promote PI(3,4,5)P 3 -AKT signalling and growth. In contrast, select pro-invasive IQSEC1 variants restrict PI(3,4,5)P 3 production to discrete cortical domains to form invasion-driving protrusions. Inhibition of IQSEC1 attenuates invasion in vitro and metastasis in vivo . Induction of pro-invasive IQSEC1 variants and elevated IQSEC1 expression occurs in a number of tumour types and is associated with higher-grade metastatic cancer, activation of PIP3-signalling, and predicts long-term poor outcome across multiple cancers. Spatial enrichment of phosphoinositide metabolism therefore is a switch to induce invasion over growth in response to the same external signal. Targeting IQSEC1 as the central regulator of this switch may represent a therapeutic vulnerability to stop metastasis. Spatial enrichment of PI(3,4,5)P 3 is a molecular switch to promote invasion. IQSEC1 is a GEF for ARF5/6, promoting PIP5K-dependent PI(3,4,5)P 3 production downstream of the HGF receptor Met. Pro-invasive IQSEC1 variants restrict cortical PI(3,4,5)P 3 production to subdomains that convert into invasive protrusions. IQSEC1 inhibition attenuates in vitro invasion and metastasis in vivo . IQSEC1 module is associated with poor outcome across tumour types.
Publisher: Springer Science and Business Media LLC
Date: 12-03-2021
DOI: 10.1038/S41467-021-21847-4
Abstract: The signalling pathways underpinning cell growth and invasion use overlapping components, yet how mutually exclusive cellular responses occur is unclear. Here, we report development of 3-Dimensional culture analyses to separately quantify growth and invasion. We identify that alternate variants of IQSEC1, an ARF GTPase Exchange Factor, act as switches to promote invasion over growth by controlling phosphoinositide metabolism. All IQSEC1 variants activate ARF5- and ARF6-dependent PIP5-kinase to promote PI(3,4,5)P 3 -AKT signalling and growth. In contrast, select pro-invasive IQSEC1 variants promote PI(3,4,5)P 3 production to form invasion-driving protrusions. Inhibition of IQSEC1 attenuates invasion in vitro and metastasis in vivo. Induction of pro-invasive IQSEC1 variants and elevated IQSEC1 expression occurs in a number of tumour types and is associated with higher-grade metastatic cancer, activation of PI(3,4,5)P 3 signalling, and predicts long-term poor outcome across multiple cancers. IQSEC1-regulated phosphoinositide metabolism therefore is a switch to induce invasion over growth in response to the same external signal. Targeting IQSEC1 as the central regulator of this switch may represent a therapeutic vulnerability to stop metastasis.
Publisher: Springer Science and Business Media LLC
Date: 15-02-2017
DOI: 10.1038/NCOMMS14206
Abstract: The secretome of cancer and stromal cells generates a microenvironment that contributes to tumour cell invasion and angiogenesis. Here we compare the secretome of human mammary normal and cancer-associated fibroblasts (CAFs). We discover that the chloride intracellular channel protein 3 (CLIC3) is an abundant component of the CAF secretome. Secreted CLIC3 promotes invasive behaviour of endothelial cells to drive angiogenesis and increases invasiveness of cancer cells both in vivo and in 3D cell culture models, and this requires active transglutaminase-2 (TGM2). CLIC3 acts as a glutathione-dependent oxidoreductase that reduces TGM2 and regulates TGM2 binding to its cofactors. Finally, CLIC3 is also secreted by cancer cells, is abundant in the stromal and tumour compartments of aggressive ovarian cancers and its levels correlate with poor clinical outcome. This work reveals a previously undescribed invasive mechanism whereby the secretion of a glutathione-dependent oxidoreductase drives angiogenesis and cancer progression by promoting TGM2-dependent invasion.
Location: United States of America
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Shehab Ismail.